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rs200893856

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BS1_Supporting

The NM_005076.5(CNTN2):​c.821G>A​(p.Arg274His) variant causes a missense change. The variant allele was found at a frequency of 0.0000837 in 1,612,488 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R274C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000081 ( 1 hom. )

Consequence

CNTN2
NM_005076.5 missense

Scores

3
7
4

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.30
Variant links:
Genes affected
CNTN2 (HGNC:2172): (contactin 2) This gene encodes a member of the contactin family of proteins, part of the immunoglobulin superfamily of cell adhesion molecules. The encoded glycosylphosphatidylinositol (GPI)-anchored neuronal membrane protein plays a role in the proliferation, migration, and axon guidance of neurons of the developing cerebellum. A mutation in this gene may be associated with adult myoclonic epilepsy. [provided by RefSeq, Sep 2016]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP2
?
    PP2 - Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease
Missense variant where missense usually causes diseases, CNTN2
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000105 (16/152160) while in subpopulation SAS AF= 0.000207 (1/4828). AF 95% confidence interval is 0.0000905. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CNTN2NM_005076.5 linkuse as main transcriptc.821G>A p.Arg274His missense_variant 8/23 ENST00000331830.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CNTN2ENST00000331830.7 linkuse as main transcriptc.821G>A p.Arg274His missense_variant 8/231 NM_005076.5 P1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000105
AC:
16
AN:
152160
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000865
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000162
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000128
AC:
32
AN:
249638
Hom.:
0
AF XY:
0.000111
AC XY:
15
AN XY:
134942
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000870
Gnomad ASJ exome
AF:
0.000300
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.000196
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000160
Gnomad OTH exome
AF:
0.000165
GnomAD4 exome
AF:
0.0000815
AC:
119
AN:
1460328
Hom.:
1
Cov.:
31
AF XY:
0.0000991
AC XY:
72
AN XY:
726294
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000448
Gnomad4 ASJ exome
AF:
0.0000767
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000278
Gnomad4 FIN exome
AF:
0.0000375
Gnomad4 NFE exome
AF:
0.0000756
Gnomad4 OTH exome
AF:
0.0000663
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000105
AC:
16
AN:
152160
Hom.:
0
Cov.:
33
AF XY:
0.000135
AC XY:
10
AN XY:
74328
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.000865
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000162
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000161
Hom.:
0
Bravo
AF:
0.000125
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
?
    Exome Aggregation Consortium database
AF:
0.000148
AC:
18
EpiCase
AF:
0.000164
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 14, 2021The c.821G>A (p.R274H) alteration is located in exon 8 (coding exon 7) of the CNTN2 gene. This alteration results from a G to A substitution at nucleotide position 821, causing the arginine (R) at amino acid position 274 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Epilepsy, familial adult myoclonic, 5 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeOct 24, 2022This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 274 of the CNTN2 protein (p.Arg274His). This variant is present in population databases (rs200893856, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CNTN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 474492). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CNTN2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Uncertain
0.057
T
BayesDel_noAF
Uncertain
0.12
CADD
Pathogenic
34
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.30
T;T;.
Eigen
Pathogenic
0.69
Eigen_PC
Pathogenic
0.68
FATHMM_MKL
Uncertain
0.96
D
M_CAP
Uncertain
0.089
D
MetaRNN
Uncertain
0.55
D;D;D
MetaSVM
Uncertain
-0.089
T
MutationAssessor
Benign
1.5
L;L;.
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.62
T
Polyphen
1.0
D;D;.
Vest4
0.72
MVP
0.92
MPC
1.4
ClinPred
0.49
T
GERP RS
5.5
Varity_R
0.66
gMVP
0.46

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.11
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs200893856; hg19: chr1-205030396; COSMIC: COSV59348313; COSMIC: COSV59348313; API